The work is geared towards understanding the structure, function, and dynamics of biologically-relevant systems. Specifically, computer time is requested to reach the following goals: (1) We propose to use molecular dynamics (MD) simulations to probe the mechanism by which fusion inhibiting and fusion peptides carry out their function. We have already carried out MD simulations on bilayer systems including a system that contains the experimentally well characterized tripeptide Ala-Phe-Ala. Our work on the Ala-Phe-Ala system has been quite successful in reproducing the positioning of this peptide in the bilayer as well as reproducing the order parameters of nearby lipid alkyl chains. Given our ability to model this well characterized system effectively we will proceed to study small peptides that either facilitate or inhibit fusogenic activity. (2) Coupled density functional Hamiltonians/molecular mechanics (DF/MM) and semiempirical/molecular mechanics (S/MM) methods will be used to study a reaction mechanism in solution as well as in an enzyme active site. We have recently developed both of these methods within our laboratory and have published preliminary work using the DF/MM model. With the S/MM method we have been able to successfully model the zinc-water and zinc-hydroxide form of human carbonic anhydrase IJ (HCAII), which sets the stage for our studies on proton transfer out of the HCAII active site. With the DF/MM method we will study the reaction of formaldehyde + hydroxide as a model reaction for the catalytic mechanism of the scrine proteases. In general, these methods represent an exciting new technique that will give molecular-level details regarding reactions in solution and in enzyme active sites.